Study On The Associations Between Single Nucleotide Polymorphisms And Radiotherapy Response And Survival In Esophageal Cancer Patients

Background & Aims:Cancer patients receiving radiotherapy alone or in combination with other treatment display a large patient-to-patient variability in their treatment response and survival. Single nucleotide polymorphisms (SNPs) are the most common genetic variations. SNPs can alter the amino acid sequence of the encoded proteins, or alter RNA splicing and gene transcription, resulting in either increased or decreased expression or activity of the encoded protein. SNPs may contribute to individual suscepitbulity and the variability of radiotherapy or druge response. Our study was to investigate the associations between genetic variations in radiosensitivity genes and the treatment response and survival in esophageal cancer patients treated with preoperative radiotherapy followed by esophagectomy.Methods:This retrospective study included 246 histologically confirmed esophageal cancer patients treated with preoperative radiotherapy followed by esophagectomy from The Cancer Hospital of Chinese Academy of Medical Sciences between 1980 and 2007. Radiotherapy was administered as computed tomographic simulation to the anterior and posterior fields for about DT 40Gy/20F/4wks. Patients underwent esophagectomies approximately 4-8weeks after radiotherapy. Study end points were radiotherapy response and survival. Genomic DNA was extracted from paraffin slides of the patients. Thirty-one polymorphisms were genotyped by the Sequenom MassARRAY system. The associations between overall survival of esophageal patients and genetic variations were estimated by applying Cox proportional hazards models. The Kaplan-Meier survival function and log-rank tests were used to assess survival in relation to individual polymorphisms. For pathologic response to therapy, unconditional multivariate logistic regression analysis was done to estimate adjusted odds ratios (ORs) along with the corresponding 95% confidence intervals (CIs) for each polymorphism.Results:Histology distribution was 100% squamous cell carcinoma (246 cases). The median follow-up time was 97.0 months. There were 192 deaths (78.0%) and 73 recurrences (29.7%) by the last follow-up time in the end of 2009. Overall median survival was 28.0 months. In recently study, from selected 31 candidate SNPs, ATM-111G/A, XPC Ala499Val, TGFβ-509T/C were significantly associated with the radiotherapy response in esophageal cancer patients treated with preoperative radiotherapy followed by esophagectonmy. Compared with ATM-111AA genotype, AG or GG genotypes were significantly associated with poor trentment response (Odds ratio, 0.52; 0.30 to 0.89), and compared with TGFβ-509TT genotype, TC or CC genotypes were significantly associated with poor trentment response (OR,0.50; 95% CI,0.25 to 0.98), while better response were significantly associated with CT or TT genotypes for XPC Ala499Val (OR,3.27; 95% CI,1.26 to 8.51). We also found other seven SNPs including FAS-670G/A, APE1-141T/G, APE1 Asp148Glu, XRCC1 Arg280His, ERCC1 Asn118Asn, XPD Lys751Gln and CCND1 Pro241Pro might be associated with the radiotherapy response in esophageal cancer patients. Othervise, we found three SNPs including COX-2-1195A/G, XPD Lys751Gln and CCND1 Pro241Pro genetic variations were significantly associated with poor survival. COX-2-1195 GG genotype was associated with shorter median survival time compared with TT genotype [18.9 months (95% CI,10.3 to 27.5) versus 35.3 months (95% CI,12.7 to 57.9), P=0.014]. Compared with TT genotype, Cox proportional model analyses showed that the adjusted hazard ratio of death for GG genotype was increased (HR,1.68,95% CI,1.03 to 2.74). XPD Lys751Gln GG genotype was associated with shorter survival time compared with the TT genotype [7.2 months (95% CI,5.9 to 8.6) versus 34.1 months (95% CI,20.9 to 46.0), P = 0.002]. The adjusted hazard ratio of death for GG genotype was 2.94 (95% CI,1.37 to 6.30). CCND1 Pro241Pro AA genotype was associated with shorter survival time compared with the GG genotype (P=0.027), and the adjusted hazard ratio of death for AA genotype was 1.58 (95% CI,1.02 to 2.46). COX-28473T/C and TGFβ-509T/C genetic variations were significantly associated with improved survival. Median survival of COX-28473 TT and TC genotype were 21.3 months and 52.3 months, and the adjusted hazard ratio of death for TC or CC genotype was reduced (HR,0.60; 95% CI, 0.40 to 0.91). Compared with TGFβ-509 TT genotype, the adjusted hazard ratio of death for CC genotype was reduced (HR,0.60; 95% CI,0.38 to 0.96).Conclusions:Several biologically plausible associations between individual single nucleotide polymorphisms in the radiosensitivity genes and clinical outcomes were found. These results support the hypothesis that SNPs may contribute to individual variability of radiotherapy response. Our data strongly suggest that those polymorphisms may be potential predictive markers of survival and radiotherapy response in esophageal cancer patients treated with preoperative radiotherapy followed by esophagectomy.